1. Hallmarks of Cancer Six fundamental changes 1.Self sufficiency in growth factors 2.Insensitivity to growth-inhibitory signals 3.Evasion of apoptosis 4.Limitless replicative potential 5.Sustained angiogenesis 6.Ability to invade and metastasize

4. Evasion of Apoptosis CD95 is reduced in HCC Some tumors have high level of protein that bind to death inducing signals complex &that prevent the activation of caspase 8 BCL2 activation in Burkitt lymphoma in the translocation of chromosome t(14:18) helps in protecting lymphocytes from apoptosis

5. Limitless Replicative Potential Most normal human cells have a capacity of 60-70 doubling, after the cell will enter non replicative senescence & result in shortening of telomeres at the end of chromosome & loss of telomeres beyond a certain point will lead to massive chrosomal abnormalities & death In order to develop tumor, need to maintain cells i.e. avoid cell senescence This is done by enzyme TOLEMERASE which maintain chromosome length 85-95% of cancer have up regulation of enzyme telomerase

7. Development of Sustained Angiogenesis Tumors cannot enlarge beyond 1-2 mm thickness unless they are vascularized, hypoxia will induce apoptosis by activation of TP53. Angiogenesis is required for tumor growth & metastasis. Tumor-associated angiogenic factors may be produced by the tumor or by inflammatory cells TP53 inhibit angiogenesis by stimulation of anti-angiogenesis molecules VEGF is under the control of RAS oncogene. Proteases are involved in regulating angiogenic & antiangiogenic factors.

8. Ability to Invade & Metastasize 1)Invasion of extracellular matrix 2)Vascular dissemination & homing of tumor cells

9. Tumor cells binds to leukocytes, this protect them from host defense mechanisms Tumor cells adhere to vascular endothelium & pass through BM Site of extravasations & Meyts depends on: -Blood & Lymphatic supply -Organ tropism/adhesion molecules -Some tumors have increase CXcr4 and its legends is only seen in sites of breast Mets NOT ALL SITES CAN BE PREDICTED

12. Genomic Instability-Enabler Of Malignancy BRCA1&BRCA2 mutation in 80% of familial breast ca, BRCA1&BRCA2 mutation in males & females increase risk of breast, prostate,ovaries,pancrease,bile duct, & melanocytes Females with BRCA1 mutation are at higher risk of developing ovarian ca & males are at higher risk of prostate ca

13. Molecular Basis of multistep carcinogenesis

14. Neoplastic transformation is a progressive process involving multiple “hits” or genetic changes. Accumulation of multiple mutations since we need six fundamental changes Evidence is both Epidemiologic: cancer increase with age Molecular : cancers analyzed show multiple genetic mutations

15. Molecular Basis of multistep carcinogenesis Alterations in DNA cause changes in one or both of the following types of genes: –Proto-oncogenes –Tumor suppressor genes Best example is colonic cancer APC  RAS  18q  p53

16. Molecular Basis of Multistep Carcinogenesis

17. Tumor Progression & Heterogeneity Tumor progression: means increase aggressiveness & and is acquired occurring in an increasing fashion Development of new subset of cells that are different in aspects such as invasivness,ability to Mets, hormonal response-  Heterogeneous group Results from multiple mutations occurring independently in different cells  subclone of cells that is different

19. Karyotypic changes in tumor The genetic damage range from point mutations to chromosomal changes Translocation:t(22:9) in CML t(8:14) in Burkitt’s t(14:18) F. Lymphoma Deletions: 13q14 retinoblastoma 17p,5q colon ca Gene amplification N-myc neuroblastoma Her-2 Breast ca